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A pan-European study of the C9orf72 repeat associated with FTLD : geographic prevalence, genomic instability, and intermediate repeats

(2013) HUMAN MUTATION. 34(2). p.363-373
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Abstract
We assessed the geographical distribution of C9orf72 G4C2 expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n=1,205), ascertained by the European Early-Onset Dementia (EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (724 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss-of-function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the G4C2 repeat in C9orf72 expansion carriers (P<0.001) with the most common indel creating one long contiguous imperfect G4C2 repeat, which is likely more prone to replication slippage and pathological expansion.
Keywords
repeat expansion, intermediate alleles, FTLD, C9orf72, AMYOTROPHIC-LATERAL-SCLEROSIS, European Early-Onset Dementia consortium, FRONTOTEMPORAL LOBAR DEGENERATION, GGGGCC HEXANUCLEOTIDE REPEAT, MOTOR-NEURON DISEASE, CHROMOSOME 9P, PATHOLOGICAL FEATURES, EXPANSION, DEMENTIA, ALS, FTD

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Citation

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Chicago
van der Zee, Julie, Ilse Gijselinck, Lubina Dillen, Tim Van Langenhove, Jessie Theuns, Sebastiaan Engelborghs, Stéphanie Philtjens, et al. 2013. “A pan-European Study of the C9orf72 Repeat Associated with FTLD : Geographic Prevalence, Genomic Instability, and Intermediate Repeats.” Human Mutation 34 (2): 363–373.
APA
van der Zee, J., Gijselinck, I., Dillen, L., Van Langenhove, T., Theuns, J., Engelborghs, S., Philtjens, S., et al. (2013). A pan-European study of the C9orf72 repeat associated with FTLD : geographic prevalence, genomic instability, and intermediate repeats. HUMAN MUTATION, 34(2), 363–373.
Vancouver
1.
van der Zee J, Gijselinck I, Dillen L, Van Langenhove T, Theuns J, Engelborghs S, et al. A pan-European study of the C9orf72 repeat associated with FTLD : geographic prevalence, genomic instability, and intermediate repeats. HUMAN MUTATION. 2013;34(2):363–73.
MLA
van der Zee, Julie, Ilse Gijselinck, Lubina Dillen, et al. “A pan-European Study of the C9orf72 Repeat Associated with FTLD : Geographic Prevalence, Genomic Instability, and Intermediate Repeats.” HUMAN MUTATION 34.2 (2013): 363–373. Print.
@article{3212306,
  abstract     = {We assessed the geographical distribution of C9orf72 G4C2 expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n=1,205), ascertained by the European Early-Onset Dementia (EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98\% in overall FTLD, with 18.52\% in familial, and 6.26\% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33\% and 20.73\%, but also Spain with 25.49\%. In contrast, prevalence in Germany was limited to 4.82\%. In addition, we studied the role of intermediate repeats (724 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss-of-function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the G4C2 repeat in C9orf72 expansion carriers (P{\textlangle}0.001) with the most common indel creating one long contiguous imperfect G4C2 repeat, which is likely more prone to replication slippage and pathological expansion.},
  author       = {van der Zee, Julie and Gijselinck, Ilse and Dillen, Lubina and Van Langenhove, Tim and Theuns, Jessie and Engelborghs, Sebastiaan and Philtjens, St{\'e}phanie and Vandenbulcke, Mathieu and Sleegers, Kristel and Sieben, Anne and B{\"a}umer, Veerle and Maes, Githa and Corsmit, Ellen and Borroni, Barbara and Padovani, Alessandro and Archetti, Silvana and Perneczky, Robert and Diehl-Schmid, Janine and de Mendon\c{c}a, Alexandre and Miltenberger-Miltenyi, Gabriel and Pereira, S{\'o}nia and Pimentel, Jos{\'e} and Nacmias, Benedetta and Bagnoli, Silvia and Sorbi, Sandro and Graff, Caroline and Chiang, Huei-Hsin and Westerlund, Marie and Sanchez-Valle, Raquel and Llado, Albert and Gelpi, Ellen and Santana, Isabel and Almeida, Maria Ros{\'a}rio and Santiago, Beatriz and Frisoni, Giovanni and Zanetti, Orazio and Bonvicini, Cristian and Synofzik, Matthis and Maetzler, Walter and M{\"u}ller vom Hagen, Jennifer and Sch{\"o}ls, Ludger and Heneka, Michael T and Jessen, Frank and Matej, Radoslav and Parobkova, Eva and Kovacs, Gabor G and Str{\"o}bel, Thomas and Sarafov, Stayko and Tournev, Ivailo and Jordanova, Albena and Danek, Adrian and Arzberger, Thomas and Fabrizi, Gian Maria and Testi, Silvia and Salmon, Eric and Santens, Patrick and Martin, Jean-Jacques and Cras, Patrick and Vandenberghe, Rik and De Deyn, Peter Paul and Cruts, Marc and Van Broeckhoven, Christine},
  issn         = {1059-7794},
  journal      = {HUMAN MUTATION},
  language     = {eng},
  number       = {2},
  pages        = {363--373},
  title        = {A pan-European study of the C9orf72 repeat associated with FTLD : geographic prevalence, genomic instability, and intermediate repeats},
  url          = {http://dx.doi.org/10.1002/humu.22244},
  volume       = {34},
  year         = {2013},
}

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